Sains Malaysiana 47(3)(2018): 517–522

http://dx.doi.org/10.17576/jsm-2018-4703-11

Kajian Dok Molekul Mengenai Interaksi antara RNA-Bergantung RNA Polimerase Virus Denggi dan Analog Nukleosida

(Molecular Docking Study of the Interactions between Dengue Virus RNA-Dependent-RNA

Polymerase and Nucleoside Analogues)

NOR NADIRAH ABDULLAH, KAMAL RULLAH, LAM KOK WAI & MALINA JASAMAI*

Drugs & Herbal Research Centre, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Wilayah Persekutuan, Malaysia

Received: 8 June 2017/Accepted: 24 October 2017

ABSTRAK

Enzim RNA-bergantung RNA polimerase adalah sasaran dadah yang menarik untuk mengubati jangkitan denggi. Analog nukleosida menyerupai substrat asal enzim polimerase. Ia bertindak sebagai perencat atau substrat kepada enzim ini lalu menyebabkan penamatan pramatang bebenang DNA/RNA atau penghasilan DNA/RNA yang rosak. Ini akan menghentikan proses replikasi virus. Kajian dok molekul untuk mengenal pasti interaksi molekular antara enzim dan ligannya telah dilakukan berdasarkan maklumat yang diperoleh berkenaan struktur kristal domain RdRp. Tapak pengikat-ligan domain RdRp yang terdiri daripada sisa asid amino Asn492, Asn405, Lys401, Thr605 dan Gly601 telah dikenal pasti setelah pengedokan analog nukleosida yang boleh didapati secara komersial dijalankan. Pengedokan analog nukleosida yang menyerupai substrat asal RdRp ke dalam tapak pengikat menunjukkan mod pengikat-ligan dengan ikatan hidrogen, aromatik-π dan interaksi cas adalah interaksi utama yang terlibat. Kajian ini juga memberi maklumat berkenaan farmakofor analog nukleosida yang boleh digunakan dalam reka-bentuk dadah berasaskan struktur terhadap sasaran penting ini.

Kata kunci: Analog nukleosida; dok molekul; enzim RdRp; tapak pengikat-ligan; virus denggi

ABSTRACT

RNA-dependent RNA polymerase (RdRp) enzyme is an attractive drug target to treat dengue infection. Nucleoside analogues are mimics of natural substrates for polymerase enzymes. They act as inhibitors or substrates for these enzymes resulted in the premature termination of the DNA/RNA strands or formation of faulty DNA/RNA strands. This will halt the virus replication process. Based on the published crystal structure of RdRp domain, docking study to identify molecular interactions between the enzyme and its ligands were performed. Docking of the commercially available nucleoside analogues identified the ligand-binding pocket of the RdRp domain encompasses of Asn492, Asn405, Lys401, Thr605 and Gly601 amino acid residues. Docking of the nucleoside analogues, mimics of the natural substrate for RdRp into this pocket showed the ligand-binding mode, in which hydrogen bonding, π-aromatic and charge interactions are the main forces involved. This study also showed the pharmacophore of the nucleoside analogues which will be useful in structure-based drug design against this important target.

Keywords: Dengue virus; ligand-binding pocket; molecular docking; nucleoside analogues; RdRp enzyme

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*Corresponding author; email: malina@ukm.edu.my